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Lgr5-Mediated Restraint of Β-Catenin Is Essential for B-Lymphopoiesis and Leukemia-Initiation

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Lgr5-Mediated Restraint of Β-Catenin Is Essential for B-Lymphopoiesis and Leukemia-Initiation bioRxiv preprint doi: https://doi.org/10.1101/2020.03.12.989277; this version posted March 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Letter February 5, 2020 2020-02-01971B Lgr5-mediated restraint of β-catenin is essential for B-lymphopoiesis and leukemia-initiation Kadriye Nehir Cosgun1, Mark E. Robinson1, Gauri Deb1, Xin Yang2, Gang Xiao1, Teresa Sadras1, Jaewoong Lee1, Lai N. Chan1, Kohei Kume1, Maurizio Mangolini3, Janet Winchester1, Zhengshan Chen1, Lu Yang1, Huimin Geng2, Shai Izraeli1,4, Joo Song5, Wing-Chung Chan5, Andrew G. Polson6, Hassan Jumaa7, Hans Clevers8 & Markus Müschen1 1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA 91016 2Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143 3Department of Haematology, Cambridge University, Cambridge, UK 4 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 5Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 6Genentech, Inc., South San Francisco, CA 94080 7Institute for Immunology, University of Ulm, Ulm, Germany 89081 8Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Utrecht, Netherlands For correspondence: Markus Müschen, MD-PhD E-mail: [email protected] Phone: +1-626-218-5171 Department of Systems Biology, City of Hope Comprehensive Cancer Center, 1218 South Fifth Ave, Monrovia, CA 91016 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.12.989277; this version posted March 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Upon productive immunoglobulin gene rearrangement, expression of a functional pre-B cell receptor (pre-BCR) initiates positive selection of pre-B cells, clonal expansion and self-renewal1-2. Studying mechanisms driving this first wave of B-lymphopoiesis, we identified the G-protein coupled receptor Lgr5 as an essential initiator of positive selection. Lgr5 was extensively studied as determinant of stem cell populations in multiple tissues3-6, but not in B-cells. While undetectable throughout the hematopoietic system, positively selected pre-B cells were marked with a sharp peak of Lgr5 expression. Conditional deletion of Lgr5 preceding the pre-BCR checkpoint induced negative selection and complete abortion of B-cell development. Proteomic studies of Lgr5-ablation revealed massive (>250-fold) accumulation of -catenin and suppression of MYC. Lgr5-deficient pre-B cells fully recovered by concurrent -catenin-deletion, demonstrating a central role of Lgr5-mediated restraint of -catenin at the pre-BCR checkpoint. In other cell types, -catenin/TCF4 complexes drive transcriptional activation of MYC7-9. Instead of TCF4, proximity-based interactome studies in pre-B cells identified the B- lymphoid transcription factors IKZF1 and IKZF310-11 as -catenin-binding partners, which had the opposite effect and caused transcriptional repression of MYC. On positively selected pre-B cells, Lgr5 prevented accumulation of -catenin and formation of complexes with IKZF1 and IKZF3, which relieved transcriptional repression of MYC. Activating β-catenin-mutations are common throughout all main types of cancer7-8, but were conspicuously absent in pre-B leukemia (B-ALL). Like pre-B cells, B- ALL cells were uniquely sensitive to genetic and pharmacological β-catenin hyperactivation, which recapitulated the effects of Lgr5-deletion and compromised colony formation and leukemia-initiation. A new LGR5 antibody-drug conjugate targeted leukemia-initiating cells in patient-derived B-ALL and achieved long-term disease-control. Likewise, small molecule hyperactivation of -catenin selectively killed B-ALL but not other cell types. Hence, Lgr5-mediated restraint of -catenin activation is essential for B-lymphopoiesis and revealed an unexpected vulnerability that can be leveraged for the treatment of drug-resistant B-ALL. Lgr5 is essential for the initiation of B-lymphopoiesis Once early B-lymphocyte precursors have productively rearranged immunoglobulin (Ig) V, D and J gene segments, expression of a functional Ig -heavy chain as part of the pre-B cell receptor (pre-BCR) results in a strong positive selection signal to initiate clonal expansion and the first wave of B-lymphopoiesis1, 2. To study mechanisms of positive selection and pre-B cell self-renewal, we analyzed gene expression changes that are induced at the onset of Ig -heavy chain signaling. Among the most prominent changes at the pre-BCR checkpoint, we identified upregulation of the Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5; Fig. 1a and b, Extended data figure 1a). While mRNA levels of Lgr5 were low or undetectable 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.12.989277; this version posted March 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. throughout the entire spectrum of hematopoietic lineages, the pre-BCR checkpoint was marked by a sharp peak of Lgr5 expression (Hardy Fractions C-D; Fig. 1c, Extended data figure 1b-c). Lgr5 was extensively studied as determinant of adult stem cell populations in multiple tissues including intestinal3, kidney, liver4 and gastric tissues as well as ear and hair follicles5. For instance, in the colon crypt, Lgr5 marks quiescent stem cell populations that promote tissue regeneration and give rise to the main lineages of the colon epithelium6. Mechanistically, Lgr5 is thought to interact with Rspo1 to potentiate WNT signaling by stabilizing Frizzled (FZD) surface receptors of WNT12, induce assembly of disheveled (DVL2)13-16 and -arrestin (ARRB2)17-20 scaffolds, which ultimately results in accumulation of -catenin. A role of Lgr5 was not previously examined in B-lymphocyte development. To study the functional significance of sharp upregulation of Lgr5 at the pre-BCR checkpoint (Hardy Fractions C-D), we tested the consequences of inducible Cre-mediated deletion of Lgr5 in developing pre-B cells. Under cell culture conditions, inducible Lgr5-deletion caused rapid loss of competitive fitness of pre-B cells (Fig. 1d). In a conditional mouse model for deletion of Lgr5 from earliest stages of B-cell development (Mb1-Cre), pro-B cells (Hardy Fractions A-B) developed normally. However, B cell precursors could not progress past the pre- BCR checkpoint resulting in complete abortion of B-cell development in these mice (Fig. 1e-f, Extended data figure 2). Even deletion of only one allele of Lgr5 was sufficient to cause near-complete ablation of B-cell development, suggesting that even moderate reduction of Lgr5 gene expression may compromise positive selection at the pre-BCR checkpoint (Fig. 1e-f, Extended data figure 2). Interestingly, while deletion of Lgr5 compromised B-lymphopoiesis in vivo and competitive fitness in vitro, loss of Lgr5 did not significantly increase apoptosis and cell death (Extended data figure 9d, f). In addition, when deletion of Lgr5 was induced in mature B-cells after the pre-BCR checkpoint (Cd21-Cre; Extended data figure 3) or in germinal center B- cells (Aicda-Cre; Extended data figure 4), loss of Lgr5 only caused a modest reduction of marginal zone B- cells. All other mature B-cell subsets, including B1 cells remained unaffected. Lgr5-deficient germinal center (GC) B-cells underwent normal affinity maturation and were able to develop antigen-specific B cells in response to immunization (Extended data figure 4). Consistent with a sharp peak of gene expression in pre- B cells (Hardy Fractions C-D), these findings indicate that Lgr5 is uniquely required for positive selection at the pre-BCR checkpoint. Once mature B-cell populations have formed, they no longer depend on Lgr5 function for maintenance and affinity maturation in humoral immune responses. Lgr5 expression predicts poor clinical outcomes in patients with B-ALL While Lgr5 contributes to self-renewal of normal epithelial stem cells and tissue regeneration, this is also the case for cancer-initiating cells. For instance, lineage-tracing experiments revealed Lgr5 as determinant of tumor-initiation in intestinal adenomas21. In addition, Lgr5 marks colon cancer-initiating cells22, promotes metastasis23 and represents a therapeutic target for eradication of colon cancer stem cells (NCT02726334, 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.12.989277; this version posted March 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. NCT03526835)24, 25. For this reason, we studied LGR5 mRNA levels in patient-derived samples of B-cell acute lymphoblastic leukemia (B-ALL), the tumor that originates from pre-B cells, compared to common solid tumors and hematopoietic malignancies. While LGR5 is expressed in multiple solid tumors, including colon cancer,
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